?Development and Application of a Porcine Model of Pancreatic Cancer? PROJECT SUMMARY/ABSTRACT The long-term goal of this research is to develop a platform on which experimental therapies for pancreatic cancer can be advanced to the clinic in a more efficient manner than achievable with current preclinical pancreatic cancer models. The focused objective of this R01 application is to develop a genetically-defined, autochthonous model of pancreatic adenocarcinoma in immunocompetent pigs, provide some validation data with respect to gross behavior, microscopy, tumor markers, genetic sequence, and transcription, and determine the model's utility for image-guided surgery. Tumors will be induced by local targeting of genes known to be associated with pancreatic cancer (namely, KRAS, p53, SMAD4, and CDKN2A), using a combination of transgenic subjects (the NSRRC Onco-pig), lentiviral-mediated in vivo gene transfer, and tumorigenic ductal cell implantation. Some murine models have failed to reflect human tumor biology because of differences in physiology, anatomy, and genetic sequence with humans. So, the rationale to build a porcine model of pancreatic cancer is that it should be more predictive of human tumor biology and response to therapy than murine models are, because swine have greater genetic and phenotypic homology with humans. The hypothesis of this R01 application is that forced expression of relevant mutant genes or transplanted tumorigenic pancreatic cells within the porcine pancreas will produce pancreatic tumors, and that this tumor model will be clinically relevant and useful. The utility of the model will be demonstrated with a comparative trial of reagents for Fluorescence Image-Guided Surgery, in experiments that would not be possible in the mouse. The work proposed in this R01 application will be accomplished through a collaborative team consisting of a general/oncologic surgeon (PI), a biomedical engineer with experience in molecule design, two molecular/cellular biologists with expertise in pancreatic cancer and gene editing, a medical oncologist who manages patients with pancreatic cancer, a pathologist specializing in pancreatic/GI cancers, sequencing and bioinformatics experts, and a biostatistician. This project is innovative because no large animal model of pancreatic cancer exists. The impact of a validated porcine model of pancreatic cancer would be to enhance, complement, and supplement preclinical data from other tumor models, and also to advance experimental anti-tumor therapies to the clinic in a more efficient manner, with fewer experimental therapies failing in clinical trials. In addition, a porcine model of pancreatic cancer could advance the design and development of minimally invasive catheters and energy sources used to ablate pancreatic tumors, and also to develop and/or improve techniques to detect, image, diagnose, and monitor these tumors.